Consider this post a continuation of the prior one on prophylaxis. I mention a bit on the pathophysiology, where adaptive immunity seems to play a key role in the way the body deals with the fungus, with mice with SCID infected with pneumocystis not being able to mount an inflammatory response. As a result of the lack of inflammatory response, they do not have significant hypoxia and are not as ill as those with neutrophils hanging around. Given our experience with COVID, I think it stands to reason that those whose humoral immune system is defective and are not able to mount an inflammatory response will not have a severe presentation. In general, patients who are HIV positive tend to have a more insidious presentation when they come in with PJP, usually having longer durations of symptoms and progressive dyspnea (1). This is in contrast with the non-HIV immunosuppressed folks that are infected with PJP, who come in after a few days of symptoms and rapidly progress to respiratory failure. The presentation in the latter is more fulminant and is associated with a higher mortality rate.
One of the earliest studies evaluated episodes of PJP in 46 patients with AIDS and 39 patients in other immunosuppressive disorders (2). While there were no differences in frequency of presenting symptoms such as subjective fever, chills, dyspnea, cough, and chest pain, AIDS patients tended to present after roughly 28 days of illness compared to 5 days in the non-AIDS group (p=0.0001). Moreover, more patients in the non-AIDS group were febrile (92% vs 76%) and had a higher respiratory rate (26 vs 24), but AIDS patients were more likely to be hypoxic at room air and have lower A-a gradients (41 mmHg vs 59mmHg in the AIDS and non-AIDS, respectively). Histological analysis revealed that fungal density was lower in the non-AIDS group, with that group having 12/32 patients being quantified as having “few” fungi, compared to 3/30 in the AIDS group. An ICU-based study (3) evaluated 72 cases of PCP in 45 HIV positive and 27 HIV negative patients. Those patients who were HIV negative had shorter duration of symptoms prior to ICU admission, higher SAPS-II score (reflecting more severe disease), and lower P/F ratio compared to the HIV-infected counterparts:
These findings were confirmed in a large, multicenter cohort of 544 patients (4). 223 of these patients had AIDS, with duration of symptoms in that group being longer compared to the non-HIV group. Further, the latter group were more likely to present with shock:
The difference in the presentation, as noted earlier, may be due to the more robust inflammatory response in the non-HIV patients. Why this is the case is beyond my intelligence and pay grade, but bronchoalveolar lavage studies may help support this idea. For instance, in one cohort (3) 81% of HIV positive patients had a high density of PJP compared to 35% of the non-HIV patients. Neutrophil count off BAL was higher in HIV-negative patients (65,475) compared to HIV-positive patients (24750). A retrospective study of 109 patients confirmed this finding using PJP PCR, with non-HIV patients having lower fungal loads based on the Ct value, shorter duration between symptom onset and treatment (7 days vs 30 days), and higher rates of hypoxia (95% vs 80%) compared to the HIV-infected patients. Finally, a retrospective cohort of 75 patients (6) found that serum BD glucan (107.1 vs 30.5, p <0.001) and Grocott stain positivity (73% vs 4.3%) were higher in the HIV-positive cohort compared to the HIV-negative cohort, both reflecting a higher fungal load.
If there is a higher degree of inflammation and higher rates of hypoxemia in the non-HIV patients, this would likely translate to worse outcomes. Unfortunately, this is what typically happens. Whether this is because people do not identify PJP in this population and start therapy later or a dysregulated immune response is unclear to me. Regardless, this is the pattern typically seen. For instance, one retrospective study (6) found that survival was statistically lower in the HIV-negative group:
A single center retrospective study of 42 patients with PJP found higher mortality at 60 and 90 days in the non-HIV group, with a higher percentage of patients in the non-HIV group presenting with shock, though this was not statistically significant (7):
A previously cited ICU study (3) had similar findings. Mortality was higher in the HIV-negative cohort, especially when looking at those who required mechanical ventilation (62% in the HIV-negative cohort compared to 29% in HIV-positive cases, p=0.0002), with more patients in the non-AIDS group progressing to ARDS:
Multivariate analysis revealed that negative HIV status (OR 3.73, 95% CI 1.10 to 12.60) and SAPS II score (OR 1.07, 95% CI 1.02 to 1.12) were associated with higher mortality. A larger retrospective study of 424 patients found that HIV negative folks were older and had a higher mortality as well (8):
Again, this was confirmed in a larger cohort study, with more non-HIV patients requiring mechanical ventilation, ICU admission, immediate oxygen therapy, and higher mortality (4):
With multivariate analysis finding that HIV infection and SOT were protective of mortality, though allogeneic HSCT and time to PCP treatment were associated with higher mortality:
That last part was confirmed in another study, finding ICU admission, intubation, and mortality being higher in the non-HIV group (9):
Steroids in non-HIV Patients
The use of steroids in non-AIDS patients is not quite clear cut, though the UpToDate does recommend its use. While it may seem this would be a no brainer, the data is scant and conflicting. For instance, multivariate analysis from a retrospective study (3) found that lymphopenia <800 and adjunctive steroid use were associated with higher mortality:
A small retrospective study of 31 patients found that steroid therapy did not improve mortality or need for mechanical ventilation in non-HIV patients, but there was a trend towards benefit in patients who had a high burden of pneumocystis (10):
A larger study (11) used propensity score matching to evaluate early corticosteroid (within 48 hours) therapy in non-HIV PJP patients. Matching 2:1, early corticosteroids cause a higher mean reduction in respiratory SOFA score at day 5 but not day 7, but it did not reduce SOFA scores by a full point:
Furthermore, when looking at more clinically oriented outcomes, steroids were not associated with difference in length of stay, need for mechanical ventilation, ICU admission, or 30 day all cause mortality:
Notably, there was a trend towards worse mortality in the early steroid group:
A larger retrospective study (12) used inverse probability weights to adjust for imbalances in a Japanese population with PJP. The use of adjunctive steroids was associated with a lower mortality in patients with severe PJP (PaO2 <60mmHg), but not in those with moderate PJP:
Further, a moderate dose, usually around 0.4-0.7mg/kg/d of prednisolone equivalents was the dose most associated with this benefit:
This benefit was also seen in severe PJP patients who required mechanical ventilation, though these tended to stay in the hospital for longer (22 days vs 14 days).
Two meta-analyses were also performed on multiple retrospective studies. The earlier one did not find any mortality benefit to adjunctive steroid usage (13), however a larger one (14) that included a total of 16 trials with 2518 patients overall, corticosteroid in non-HIV PJP was associated with higher ICU mortality:
And it was also associated with higher in-hospital mortality (OR 2.14, 95% CI 1.17-2.91) and 30 day mortality (OR 1.85, 95% CI 1.2-2.84). Despite this, a subgroup analysis of patients with acute hypoxemic respiratory failure found a trend towards mortality benefit (OR 0.69, 95% CI 0.47-1.01), with the benefit seen in those patients that had respiratory failure:
Low dose steroids (1mg/kg/d of prednisolone equivalent) was non-inferior in terms of mortality when compared to high dose steroid ( >240mg prednisone equivalent), but when looking at patients with hypoxemia, low dose steroids had a higher impact on mortality when compared to the high dose steroid:
It is certainly difficult to draw any meaningful conclusions, given the retrospective nature of these studies and the widely different patient populations and lack of standardization here. At the same time, it seems physiologically reasonable to give corticosteroids to those who have severe hypoxemia, as these are the ones who tend to benefit the most from them. Based on the above, the standard prednisone taper used in PJP provides a fairly moderate amount of prednisone that is fairly tolerable.
TL;DR – see the image below (15)
- Steroids can be used in non-HIV PJP, but there is a lack of any meaningful data. Despite this, it seems those with severe hypoxemia would benefit from moderate (1mg/kg/d prednisone) amounts of steroids for a short time. How long? Idk, use the pred taper for the AIDS population, we have no answer here.
- Cillóniz C, Dominedò C, Álvarez-Martínez MJ, Moreno A, García F, Torres A, Miro JM. Pneumocystis pneumonia in the twenty-first century: HIV-infected versus HIV-uninfected patients. Expert Rev Anti Infect Ther. 2019 Oct;17(10):787-801. doi: 10.1080/14787210.2019.1671823. Epub 2019 Oct 4. PMID: 31550942.
- Kovacs JA, Hiemenz JW, Macher AM, Stover D, Murray HW, Shelhamer J, Lane HC, Urmacher C, Honig C, Longo DL, et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med. 1984 May;100(5):663-71. doi: 10.7326/0003-4819-100-5-663. PMID: 6231873.
- Monnet X, Vidal-Petiot E, Osman D, Hamzaoui O, Durrbach A, Goujard C, Miceli C, Bourée P, Richard C. Critical care management and outcome of severe Pneumocystis pneumonia in patients with and without HIV infection. Crit Care. 2008;12(1):R28. doi: 10.1186/cc6806. Epub 2008 Jan 25. Erratum in: Crit Care. 2009;13(2)407. PMID: 18304356; PMCID: PMC2374632.
- Roux A, Canet E, Valade S, Gangneux-Robert F, Hamane S, Lafabrie A, Maubon D, Debourgogne A, Le Gal S, Dalle F, Leterrier M, Toubas D, Pomares C, Bellanger AP, Bonhomme J, Berry A, Durand-Joly I, Magne D, Pons D, Hennequin C, Maury E, Roux P, Azoulay É. Pneumocystis jirovecii pneumonia in patients with or without AIDS, France. Emerg Infect Dis. 2014 Sep;20(9):1490-7. doi: 10.3201/eid2009.131668. PMID: 25148074; PMCID: PMC4178412.
- Liu CJ, Lee TF, Ruan SY, Yu CJ, Chien JY, Hsueh PR. Clinical characteristics, treatment outcomes, and prognostic factors of Pneumocystis pneumonia in non-HIV-infected patients. Infect Drug Resist. 2019 May 30;12:1457-1467. doi: 10.2147/IDR.S199761. PMID: 31239724; PMCID: PMC6554003.
- Kato H, Samukawa S, Takahashi H, Nakajima H. Diagnosis and treatment of Pneumocystis jirovecii pneumonia in HIV-infected or non-HIV-infected patients-difficulties in diagnosis and adverse effects of trimethoprim-sulfamethoxazole. J Infect Chemother. 2019 Nov;25(11):920-924. doi: 10.1016/j.jiac.2019.06.007. Epub 2019 Jul 9. PMID: 31300379.
- Almaghrabi RS, Alfuraih S, Alohaly R, Mohammed S, Alrajhi AA, Omrani AS. Pneumocystis jiroveci Pneumonia in HIV-Positive and HIV-Negative Patients: A Single-Center Retrospective Study. Tanaffos. 2019 Mar;18(3):238-243. PMID: 32411264; PMCID: PMC7210573.
- Lee HY, Choi SH, Kim T, Chang J, Kim SH, Lee SO, Kim MN, Sung H. Epidemiologic Trends and Clinical Features of Pneumocystis jirovecii Pneumonia in Non-HIV Patients in a Tertiary-Care Hospital in Korea over a 15-Year-Period. Jpn J Infect Dis. 2019 Jul 24;72(4):270-273. doi: 10.7883/yoken.JJID.2018.400. Epub 2019 Mar 26. PMID: 30918147.
- Mansharamani NG, Garland R, Delaney D, Koziel H. Management and outcome patterns for adult Pneumocystis carinii pneumonia, 1985 to 1995: comparison of HIV-associated cases to other immunocompromised states. Chest. 2000 Sep;118(3):704-11. doi: 10.1378/chest.118.3.704. PMID: 10988192.
- Delclaux C, Zahar JR, Amraoui G, Leleu G, Lebargy F, Brochard L, Schlemmer B, Brun-Buisson C. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in non-human immunodeficiency virus-infected patients: retrospective study of 31 patients. Clin Infect Dis. 1999 Sep;29(3):670-2. doi: 10.1086/598651. PMID: 10530464.
- Wieruszewski PM, Barreto JN, Frazee E, Daniels CE, Tosh PK, Dierkhising RA, Mara KC, Limper AH. Early Corticosteroids for Pneumocystis Pneumonia in Adults Without HIV Are Not Associated With Better Outcome. Chest. 2018 Sep;154(3):636-644. doi: 10.1016/j.chest.2018.04.026. Epub 2018 Apr 26. PMID: 29705221.
- Inoue N, Fushimi K. Adjunctive Corticosteroids decreased the risk of mortality of non-HIV Pneumocystis Pneumonia. Int J Infect Dis. 2019 Feb;79:109-115. doi: 10.1016/j.ijid.2018.12.001. Epub 2018 Dec 6. PMID: 30529109.
- Fujikura Y, Manabe T, Kawana A, Kohno S. Adjunctive Corticosteroids for Pneumocystis jirovecii Pneumonia in Non-HIV-infected Patients: A Systematic Review and Meta-analysis of Observational Studies. Arch Bronconeumol. 2017 Feb;53(2):55-61. English, Spanish. doi: 10.1016/j.arbres.2016.06.016. Epub 2016 Sep 9. PMID: 27616706.
- Ding L, Huang H, Wang H, He H. Adjunctive corticosteroids may be associated with better outcome for non-HIV Pneumocystis pneumonia with respiratory failure: a systemic review and meta-analysis of observational studies. Ann Intensive Care. 2020 Mar 20;10(1):34. doi: 10.1186/s13613-020-00649-9. PMID: 32198645; PMCID: PMC7083987.
- Cordonnier C, Cesaro S, Maschmeyer G, Einsele H, Donnelly JP, Alanio A, Hauser PM, Lagrou K, Melchers WJ, Helweg-Larsen J, Matos O, Bretagne S, Maertens J; Fifth European Conference on Infections in Leukemia (ECIL-5), a joint venture of The European Group for Blood and Marrow Transplantation (EBMT), The European Organization for Research and Treatment of Cancer (EORTC), the Immunocompromised Host Society (ICHS) and The European LeukemiaNet (ELN). Pneumocystis jirovecii pneumonia: still a concern in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother. 2016 Sep;71(9):2379-85. doi: 10.1093/jac/dkw155. Epub 2016 May 12. PMID: 27550990.